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    Clinical Trial Results:
    A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of AMG 334 in Chronic Migraine Prevention

    Summary
    EudraCT number
    		 2013-001707-36
    Trial protocol
    		 DE   SE   NO   FI   DK   PL   CZ   GB  
    Global end of trial date
    28 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 May 2017
    First version publication date
    14 May 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20120295
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02066415
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen, Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Apr 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of AMG 334 compared to placebo on the change from baseline in monthly migraine days, in subjects with chronic migraine.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines, the GCPs applicable to all regions where the study was conducted and in accordance with the ethical principles set forth in the Declaration of Helsinki. All centers complied with local regulations. The study protocol and all amendments, the informed consent form, and any accompanying materials provided to subjects were reviewed and approved by an Independent Ethics Committee (IEC) or Institutional Review Board (IRB), as appropriate, at each center/country. The investigator or his/her designee informed the subject of all aspects pertaining to the subject’s participation in the study before any screening procedures were performed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 14
    Country: Number of subjects enrolled
    United States: 301
    Country: Number of subjects enrolled
    Czech Republic: 54
    Country: Number of subjects enrolled
    Denmark: 24
    Country: Number of subjects enrolled
    Finland: 38
    Country: Number of subjects enrolled
    Germany: 72
    Country: Number of subjects enrolled
    Norway: 35
    Country: Number of subjects enrolled
    Poland: 43
    Country: Number of subjects enrolled
    Sweden: 64
    Country: Number of subjects enrolled
    United Kingdom: 22
    Worldwide total number of subjects
    667
    EEA total number of subjects
    352
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    666
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 69 centers in Canada, Czech Republic, Denmark, Germany, Finland, Norway, Poland, Sweden, United Kingdom, and the United States of America (USA). The First subject was enrolled on 05 March 2014 and the last subject enrolled on 05 November 2015.

    Pre-assignment
    Screening details
    		 Of the 953 subjects screened, 286 were enrolled but not randomized; 667 subjects were randomized in a 3:2:2 ratio to receive placebo, AMG 334 70 mg, or AMG 334 140 mg. Randomization was stratified by region (North America vs Other) and medication overuse at baseline (Yes vs No).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered once a month subcutaneously by authorized investigational site study staff.

    Arm title
    		 AMG 334 70 mg
    Arm description
    		 Participants received AMG 334 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AMG 334
    Investigational medicinal product code
    AMG 334
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered once a month subcutaneously by authorized investigational site study staff.

    Arm title
    		 AMG 334 140 mg
    Arm description
    		 Participants received AMG 334 140 mg on day 1 and at weeks 4 and 8 by subcutaneous injection.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AMG 334
    Investigational medicinal product code
    AMG 334
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered once a month subcutaneously by authorized investigational site study staff.

    Number of subjects in period 1
    		Placebo AMG 334 70 mg AMG 334 140 mg
    Started
    286
    191
    190
    Received Study Drug
    282
    190
    188
    Completed
    265
    184
    182
    Not completed
    21
    7
    8
         Consent withdrawn by subject
    9
    1
    4
         Lost to follow-up
    7
    2
    2
         Decision by sponsor
    5
    4
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection.

    Reporting group title
    AMG 334 70 mg
    Reporting group description
    		 Participants received AMG 334 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection.

    Reporting group title
    AMG 334 140 mg
    Reporting group description
    		 Participants received AMG 334 140 mg on day 1 and at weeks 4 and 8 by subcutaneous injection.

    Reporting group values
    		 Placebo AMG 334 70 mg AMG 334 140 mg Total
    Number of subjects
    		 286 191 190 667
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 285 191 190 666
        From 65-84 years
    		 1 0 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.1 ( 11.3 ) 41.4 ( 11.3 ) 42.9 ( 11.1 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 226 166 160 552
        Male
    		 60 25 30 115
    Race
    Units: Subjects
        Asian
    		 4 4 0 8
        Black or African American
    		 11 10 6 27
        White
    		 268 176 184 628
        Other
    		 3 1 0 4
    Ethnicity
    Units: Subjects
        Hispanic/Latino
    		 9 7 10 26
        Not Hispanic/Latino
    		 277 184 180 641
    Prior Migraine Prophylactic Medication
    Units: Subjects
        Yes
    		 218 138 136 492
        No
    		 68 53 54 175
    Prior Migraine Prophylactic Treatment Failure
    Units: Subjects
        Yes
    		 200 127 126 453
        No
    		 86 64 64 214
    Region
    Units: Subjects
        North America
    		 135 91 89 315
        Other
    		 151 100 101 352
    Medication Overuse
    Medication overuse was defined as any of the following criteria being met during the baseline (BL) phase: • ≥ 15 days of simple analgesics (>3 days/week in each week during BL with at least 5 diary days), • ≥ 10 days of triptans (> 2 days/week in each week during BL with at least 5 diary days), • ≥ 10 days of ergots (> 2 days/week in each week during BL with at least 5 diary days), • ≥ 10 days of combination therapy intake of any combination of ergots, triptans, opiates, combination-analgesic medications or simple analgesics (> 2 days/week in each week during BL with at least 5 diary days).
    Units: Subjects
        Yes
    		 117 79 78 274
        No
    		 169 112 112 393
    Monthly Migraine Days
    A migraine day is any calendar day in which the subject experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache is defined either as a migraine without aura or a migraine with aura. Monthly migraine days are the number of migraine days in the 28-consecutive day baseline phase.
    Units: days
        arithmetic mean (standard deviation)
    		 18.22 ( 4.73 ) 17.85 ( 4.39 ) 17.78 ( 4.72 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection.

    Reporting group title
    AMG 334 70 mg
    Reporting group description
    		 Participants received AMG 334 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection.

    Reporting group title
    AMG 334 140 mg
    Reporting group description
    		 Participants received AMG 334 140 mg on day 1 and at weeks 4 and 8 by subcutaneous injection.

    Primary: Change From Baseline in Monthly Migraine Days

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    End point title
    		 Change From Baseline in Monthly Migraine Days
    End point description
    Participants recorded migraines in an eDiary on a daily basis. A migraine without aura is defined as a headache lasting continuously for ≥ 4 hours and meeting either criteria a and/or b: a) ≥ 2 of the following pain features: • Unilateral • Throbbing • Moderate to severe • Exacerbated with exercise or physical activity b) ≥ 1 of the associated symptoms: • Nausea and/or vomiting • Photophobia and phonophobia A migraine with aura met the following criteria c and d: c) ≥ 1 of the following fully reversible aura symptoms: • Visual • Sensory • Speech and/or language • Retinal • Brainstem d) Aura with, or followed by within 1 hour, headache for ≥ 4 hours. The endpoint was calculated as: Migraine days during the last 4 weeks of treatment - migraine days during the 4-week baseline phase. The endpoint was analyzed in the efficacy analysis set which includes subjects who received at least 1 dose of study drug and completed at least 1 post-baseline monthly eDiary measurement.
    End point type
    Primary
    End point timeframe
    Baseline and the last 4 weeks of the 12-week treatment period
    End point values
    		 Placebo AMG 334 70 mg AMG 334 140 mg
    Number of subjects analysed
    281
    188
    187
    Units: migraine days / month
        least squares mean (confidence interval 95%)
    -4.18 (-4.86 to -3.5)
    -6.64 (-7.47 to -5.81)
    -6.63 (-7.45 to -5.8)
    Statistical analysis title
    		 Primary Analysis of AMG 334 70 mg vs Placebo
    Statistical analysis description
    The primary endpoint was analyzed using a linear mixed effects model including treatment group, baseline value, stratification factors, scheduled visit, and the interaction of treatment group with scheduled visit. The analysis included all participants in the efficacy analysis set (656 subjects).
    Comparison groups
    Placebo v AMG 334 70 mg
    Number of subjects included in analysis
    469
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Generalized linear mixed model
    Parameter type
    		 Difference in LS means
    Point estimate
    -2.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.52
         upper limit
    		 -1.39
    Statistical analysis title
    		 Primary Analysis of AMG 334 140 mg vs Placebo
    Statistical analysis description
    The primary endpoint was analyzed using a linear mixed effects model including treatment group, baseline value, stratification factors, scheduled visit, and the interaction of treatment group with scheduled visit. The analysis included all participants in the efficacy analysis set (656 subjects).
    Comparison groups
    Placebo v AMG 334 140 mg
    Number of subjects included in analysis
    468
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Generalized linear mixed model
    Parameter type
    		 Difference in LS means
    Point estimate
    -2.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.51
         upper limit
    		 -1.38

    Secondary: Percentage of Participants with at Least a 50% Reduction in Monthly Migraine Days From Baseline

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    End point title
    		 Percentage of Participants with at Least a 50% Reduction in Monthly Migraine Days From Baseline
    End point description
    This analysis was performed using the efficacy analysis set with non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo AMG 334 70 mg AMG 334 140 mg
    Number of subjects analysed
    281
    188
    187
    Units: percentage of participants
        number (not applicable)
    23.5
    39.9
    41.2
    Statistical analysis title
    		 AMG 334 70 mg vs Placebo
    Statistical analysis description
    This endpoint was analyzed using a Cochran-Mantel-Haenszel test after the missing data were imputed as non-response, stratified by stratification factors region and medication overuse. The analysis included all participants in the efficacy analysis set (656 subjects).
    Comparison groups
    Placebo v AMG 334 70 mg
    Number of subjects included in analysis
    469
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.46
         upper limit
    		 3.27
    Statistical analysis title
    		 AMG 334 140 mg vs Placebo
    Statistical analysis description
    This endpoint was analyzed using a Cochran-Mantel-Haenszel test after the missing data were imputed as non-response, stratified by stratification factors region and medication overuse. The analysis included all participants in the efficacy analysis set (656 subjects).
    Comparison groups
    Placebo v AMG 334 140 mg
    Number of subjects included in analysis
    468
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.56
         upper limit
    		 3.51

    Secondary: Change From Baseline in Monthly Acute Migraine-specific Medication Treatment Days

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    End point title
    		 Change From Baseline in Monthly Acute Migraine-specific Medication Treatment Days
    End point description
    Monthly acute migraine-specific medication treatment days is the number of days on which migraine specific medications were used between each monthly dose of study drug. Migraine-specific medications includes two categories of medications: triptan-based migraine medications and ergotamine-based migraine medications. This analysis was performed using the efficacy analysis set.
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo AMG 334 70 mg AMG 334 140 mg
    Number of subjects analysed
    281
    188
    187
    Units: acute migraine treatment days / month
        least squares mean (confidence interval 95%)
    -1.58 (-2.05 to -1.11)
    -3.45 (-4.02 to -2.87)
    -4.13 (-4.7 to -3.56)
    Statistical analysis title
    		 AMG 334 70 mg vs Placebo
    Statistical analysis description
    This endpoint was analyzed using a generalized linear mixed model which includes treatment, visit, treatment by visit interaction, stratification factors region and medication overuse, and baseline value as covariates and assuming a first-order autoregressive covariance structure. The analysis included all participants in the efficacy analysis set (656 subjects).
    Comparison groups
    Placebo v AMG 334 70 mg
    Number of subjects included in analysis
    469
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Generalized linear mixed model
    Parameter type
    		 Difference in LS means
    Point estimate
    -1.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 -1.13
    Statistical analysis title
    		 AMG 334 140 mg vs Placebo
    Statistical analysis description
    This endpoint was analyzed using a generalized linear mixed model which includes treatment, visit, treatment by visit interaction, stratification factors region and medication overuse, and baseline value as covariates and assuming a first-order autoregressive covariance structure. The analysis included all participants in the efficacy analysis set (656 subjects).
    Comparison groups
    Placebo v AMG 334 140 mg
    Number of subjects included in analysis
    468
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Generalized linear mixed model
    Parameter type
    		 Difference in LS means
    Point estimate
    -2.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.28
         upper limit
    		 -1.82

    Secondary: Change From Baseline in Cumulative Monthly Headache Hours

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    End point title
    		 Change From Baseline in Cumulative Monthly Headache Hours
    End point description
    The cumulative duration of any qualified headache between each monthly dose of study drug regardless of acute treatment use. A qualified headache is defined as follows: • a qualified migraine headache (including an aura-only event that is treated with acute migraine-specific medication), or • a qualified non-migraine headache, which is a headache that lasts continuously for ≥ 4 hours and is not a qualified migraine headache, or • a headache of any duration for which acute headache treatment is administered. This analysis was performed using the efficacy analysis set.
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo AMG 334 70 mg AMG 334 140 mg
    Number of subjects analysed
    281
    188
    187
    Units: hours / month
        least squares mean (confidence interval 95%)
    -55.22 (-66.38 to -44.06)
    -64.76 (-78.34 to -51.17)
    -74.53 (-88.05 to -61.01)
    Statistical analysis title
    		 AMG 334 70 mg vs Placebo
    Statistical analysis description
    This endpoint was analyzed using a generalized linear mixed model which includes treatment, visit, treatment by visit interaction, stratification factors region and medication overuse, and baseline value as covariates and assuming a first-order autoregressive covariance structure. The analysis included all participants in the efficacy analysis set (656 subjects).
    Comparison groups
    Placebo v AMG 334 70 mg
    Number of subjects included in analysis
    469
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.28
    Method
    		 Generalized linear mixed model
    Parameter type
    		 Difference in LS means
    Point estimate
    -9.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.98
         upper limit
    		 7.9
    Statistical analysis title
    		 AMG 334 140 mg vs Placebo
    Statistical analysis description
    A generalized linear mixed model which includes treatment, visit, treatment by visit interaction, stratification factors region and medication overuse, and baseline value as covariates and assuming a first-order autoregressive covariance structure. The analysis included all participants in the efficacy analysis set (656 subjects).
    Comparison groups
    Placebo v AMG 334 140 mg
    Number of subjects included in analysis
    468
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 Generalized linear mixed model
    Parameter type
    		 Difference in LS means
    Point estimate
    -19.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.71
         upper limit
    		 -1.92

    Secondary: Number of Participants with Adverse Events

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    End point title
    		 Number of Participants with Adverse Events
    End point description
    Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4, where: Grade 1 = Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Grade 2 = Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL); Grade 3 = Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL; Grade 4 = Life-threatening consequences; urgent intervention indicated Grade 5 = Death related to AE. Adverse events were assessed in all randomized subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to 16 weeks after the last dose (24 weeks)
    End point values
    		 Placebo AMG 334 70 mg AMG 334 140 mg
    Number of subjects analysed
    282
    190
    188
    Units: participants
    number (not applicable)
        Any adverse event
    110
    83
    88
        Grade ≥ 2
    65
    45
    42
        Grade ≥ 3
    13
    11
    4
        Grade ≥ 4
    0
    1
    0
        Serious adverse events
    7
    6
    2
        AEs leading to discontinuation of study drug
    2
    0
    2
        Fatal adverse events
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants who Developed Antibodies to AMG 334

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    End point title
    		 Number of Participants who Developed Antibodies to AMG 334 [1]
    End point description
    Blood samples were first tested in an electrochemiluminescence (ECL)-based bridging immunoassay to detect anti-drug antibodies (ADA) against AMG 334. Samples confirmed to be positive for binding antibodies were subsequently tested in a cell-based bioassay to determine neutralizing activity against AMG 334 (Neutralizing Antibody Assay). If a sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the sample was defined as positive for neutralizing antibodies.
    End point type
    Secondary
    End point timeframe
    Weeks 2, 4, 8, 12 and 24
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analyzed in the AMG 334 treatment groups only.
    End point values
    		 AMG 334 70 mg AMG 334 140 mg
    Number of subjects analysed
    189
    187
    Units: participants
    number (not applicable)
        Binding antibody positive
    11
    3
        Neutralizing antibody positive
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug up to 16 weeks after the last dose (24 weeks)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection.

    Reporting group title
    AMG 334 140 mg
    Reporting group description
    		 Participants received AMG 334 140 mg on day 1 and at weeks 4 and 8 by subcutaneous injection.

    Reporting group title
    AMG 334 70 mg
    Reporting group description
    		 Participants received AMG 334 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection.

    Serious adverse events
    		 Placebo AMG 334 140 mg AMG 334 70 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 282 (2.48%)
    2 / 188 (1.06%)
    6 / 190 (3.16%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Fibroma
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 188 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cartilage injury
         subjects affected / exposed
    0 / 282 (0.00%)
    1 / 188 (0.53%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 188 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    1 / 282 (0.35%)
    0 / 188 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 188 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    0 / 282 (0.00%)
    1 / 188 (0.53%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 282 (0.00%)
    1 / 188 (0.53%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 282 (0.35%)
    0 / 188 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 282 (0.35%)
    0 / 188 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 282 (0.35%)
    0 / 188 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Costochondritis
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 188 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 282 (0.35%)
    0 / 188 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 188 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 282 (0.35%)
    0 / 188 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 282 (0.35%)
    0 / 188 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo AMG 334 140 mg AMG 334 70 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 282 (5.67%)
    3 / 188 (1.60%)
    6 / 190 (3.16%)
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    16 / 282 (5.67%)
    3 / 188 (1.60%)
    6 / 190 (3.16%)
         occurrences all number
    17
    3
    6

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Oct 2014
    • A DMC replaced the Data Review Team (DRT) and the Interim Analysis Review Steering Committee (IARSC). The DMC reviewed both safety data and futility analysis results. • The plans for the interim analyses were refined, and text was added to describe the 2 interim analysis time points: Interim analyses for futility will occur after approximately 65% and 80% of subjects have been randomized. • Introduced an Event Adjudication Committee, which covered the overall AMG 334 clinical development program, to ensure a thorough and systematic review and classification of all cardiovascular and cerebrovascular events that have might occurred during the studies. • US-specific protocol supplement included (Protocol Supplement Version 1.0, dated 12 February 2015) o Major change included an addition of optional novel patient-reported outcome (Migraine Physical Function Impact Diary [MPFID]) substudy for English-speaking subjects in the USA.
    23 Jul 2015
    • 2 exploratory objectives and endpoints were elevated to secondary objectives and endpoints. • The number of randomized subjects was increased from 490 to 651 subjects to increase the power for each treatment arm and to adjust for multiplicity. • The plans for the interim analyses were refined, interim analyses for futility were removed, and text was added to describe that an administrative interim analysis may be performed after all randomized subjects have completed the double-blind treatment phase. • An optional novel patient-reported outcome MPFID substudy added globally.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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